17alpha-fluoro-, 17beta-chlorofluoroacetoxy- and 17beta-methyl-delta4-and delta5-androstene derivatives



United States Patent 0 3,264,327 17ot-FLUOR0-, 17 ,B-CHLOROFLUOROACETOXY- AND 17fi-METHYL-A AND M-ANDRQSTENE DERIVATIVES Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Mar. 19, 1964, Ser. No. 353,263 Claims priority, application Mexico, July 27, 1962,

8,398 22 Claims. (Cl. 260-397) This application is a continuation-in-part of my copending patent application Serial No. 221,424, filed September 5, 1962, now abandoned.

The present invention relates to certain novel cyclopentanophenanthrene derivatives and to a method for making the same.

More particularly, this invention relates to certain novel 17a-flu0ro, 17fl-ohlorofluoroac'etoxy, and 17 8- methyl derivatives of the androstane series, represented 0 In the above formulas R represents hydrogen, lower 4 3,264,327 Patented August 2, 1966 alkyl, alkenyl or alkinyl group such as methyl, ethyl, propyl, vinyl, propenyl, ethinyl, propinyl, etc. and Z represents a single or a double-bond between 0-1 and C-2.

The present invention refers also to the corresponding 19-nor-A -compounds unsubstituted at C-1, and to certain novel 35-fiuoro, 35,17a-difiuoro, 3B-fiuoro-17fi-ch1orofluoroacetoxy and 3 B-fluoro-17o-methyl derivatives of A and A -androstenes.

The compounds of the present invention are anabolic agents with a favorable anabolic-androgenic ratio. In addition, they have antiestrogenic, anti-gonadot-rophic and anti-fibrillatory properties, lower the blood cholesterol level and inhibit the activity of the pituitary gland.

The substitition of primary and secondary hydroxyl groups by a fluorine atom has been described in the literature, for example by N. N. Yarovenko et al. in the Journal of General Chemistry of the USSR, vol. 29, 2159 (1959).

In accordance with the present invention, it has been found that the treatment of 17/3-secondary hydroxy steroids with 2-chloro-1,1,Z-trifluorotriethylamine in a suitable organic solvent produces three compounds: the 17afluoro-steroid resulting from the replacement of the hydroXy group by fluorine, with simultaneous inversion of configuration, the 17fl-ch-lorofluoroacetoxy compound and the dehydration product with migration of the 13B-methyl group.

The method for producing the 17oc-fl11010, 17f3-chlorofluoroacetoxy and 17,8-methyl-A -3-keto androstenes and the corresponding l-dehydro and l-substituted derivatives is illustrated by the following equations:

iv (1 p In the above formulas R and Z have the same meaning. 1

as heretofore indicated.

In practicing the process outlined above, the starting materials, testosterone, l-dehydro-testosterone and the cor-. responding lot-alkyl, alkenyl or alkinyl substituted de-j rivatives (I) are treated with 1 to 1.5 molar equivalents" of 2-chloro-l,1,2-trifluorotriethylamine in an inert organic solvent, at a temperature comprised between room temperature and the steam bath, for a period of time of between minutes to 3 hours. The solvent is then evaporated to dryness under vacuum, and the residue chromatographed on Florisil or neutral alumina, to produce the 17a-fluoro-(II), 17/3-chlorofluoroacetoxy-(III) and 17,8- metl1yl-A -(IV) derivatives.

Adequate solvents for this reaction are: acetonitrile,v ethers such as diethylether, isopropy-l ether, dioxane, tetrahydrofuran, Dowanol, and the like, aromatic hydrocar bons such as benzene, toluene, xylene, etc.; in general, thereaction can be carried out in any organic solvent containing no acidic hydrogen.

The A -3-keto compounds can be converted into the corresponding l-dehydro derivatives by reactionwith 2,3- dichloro-5,6-dicyano-1,4-benzoquinone.

The lu-alkyl, alkenyl and alkinyl substituted testosterones used as starting materials are obtainedby reaction of 19-hydroxy-A -androstene-3,17-dione with 2- chloro-1,1,2-trifluorotriethylamine to produce-a mixture of 5,10 methy1ene-19-nor-A -androstene-3,17-dione and 5,10 seco 5,19 cyclo B fiuoro A u androstene- 3,17-dione, which is separated by chromatography, reduction of 5, IO-methylene-19-nor-A -androstene-3,17-dione with lithium aluminum hydride to the 3,17-diol and selective oxidation at 0-3 with manganese dioxide to produce 5,10rmethylene-19-nor-A -androsten-17p-ol-3-one, reaction of this compound with a Grignard reagent and acid treatment of thus obtained 1a-substituted-S,IO-me-thylene- 19-nor-androstane componds, as described in my copending patent application Serial No. 286,931, filed June 11, 1963, now US. Patent No. 3,184,484, and Serial No. 246,074 filed February 20, 1964.

By reaction of 19-nor-testosterone with 1.1 to 1.5 molar equivalents of 2-eh-loro-1,1,Z-trifluorotriethylamine, following the same procedure as hereinbefore described for testosterone, l-dehydrotestosterone and the corresponding l-substituted derivatives, there are produced. 17a-fl1101'0- A -l9-nor-andosten-3-one, 17p-chlorofluoroacetoxy-M-l9- nor-androsten-3-one and 17/3-methyl-A -18,19-bisnorandrostadien-3-one.

The 3B,17a-difluoro-, toxyand 3fi-fluoro-17fi-methy1-A -derivatives ,of A and A -androstenes, which are also objects of the present invention, are obtained by reaction of A -androstene-3B,

4. sorbed from hexaneyonto 200 gpof Florisil. E. The fractions eluted with hexane gave.-.17/3-methyl-A -18rnorandr-ostadiene-S-One, .M.P. 112-113" 0.; [a] +69 (CHCl xmax. '238-240 m log e 4.23; 11 max. .1680

and 1620 cm.- '(enone).

Further elution *ofgthe column with ehexane-ether (9:1). afforded 17a-fluoro-A -androsten-3-one,;M.P.146-

148 C.;' [0:]D +96 (CHCl 7. max. 2404421111 log e 4.23 v max.;1685,'1615 cm.- (enone).

Further elution with hexane-ether (1:1) gave 175- chlorofluoroacetoxyrA -androsten 3 one .(testosterone (CHCl A max. 240-242 my; log 6 4.21'; v max. 1660 and 1615 (enone), 1775' and 1205 cm. (chloroflu'oroacetateester).

Example II To a solution of'2 g. of testosterone in 25. cc..of methylene chloiride,-there was added 1.1 molar equivallents of 2-chlor-o=1,1,2-trifluorotriethylamine andthe reaction mixture .was refluxed for .10 minutes under anhydrousconditions. It was then evaporated to'dryness at room temperature, under reduced pressure, and the. residue chromatographed :on 100 gqOf neutral alumina, to produce 17 8-methyl-A -l8+nor-androstadien 3-one; 17oz fluoro- A -andr'osten-3-one. and. 17 B-chlorofluoroacetoxy-A randrosten-3-0ne, identical to a the products obtained. in the preceding example- Example. III

Example I was repeated. but using tetrahydrofuran as solvent, with the same results.

Evxample IV Example I was repeated but the reaction mixture was allowed to stand at room temperature overnight. Similar results were obtained.

Example V In accordance with the method described in Example 7 I, the compounds mentioned below under I were converted into the products set forth under II, which wereseparated by chromatography.

17 3-dio1 and A -androstene-3fi,17B-diol with 2 to 2.5.

molar equivalents of the fiuorinated amine, following the' above described procedure.

By treatment of A -androsten-3B-o1-17-one with 1 to; 1.5 molar equivalents of 2-chloro-1,1,2-trifluorotriethylamine, there is produced 3B-fluoro-A -androsten-17-one.

Upon reaction of the latter compound with a Grignard reagent such as methyl magnesium bromide, vinylmag nesium bromide or ethinyl magnesium bromide, in a conventional manner, there are produced the correspond- 1 ing 3 8-fluoro-17a-alkyl, alkenyl or alkinyl substituted dey rivatives of A -androsten-17/3-ol, which are conventionally 'esterified with acid anhydrides in benzene solution and in the presence of p-toluenesulfonic acid.

The following examples serve to illustrate but are. 1

not considered to limit the scope of the present invention: 1

Example I A mixture of 3.5 g. of testosterone, 3.5 g. (1.5 molar equivalents) of 2-chloro-1,1,2-trifluorotriethylamine and 40 cc. of' anhydrous acetonitr-ile was kept at room-temperature fior 30 minutes and then evaporated to dryness in vacuo, at room temperature. The residue was ad- A dehydro-testosterone l7fl-methyl-A -18-n0r-androstatrien- 3 0ne; 17a-fiuoro-A 4-andr0stadieu-3- one; and 17 B-chlorofluoroacetoxy-A androstadien-B-one.

la-methyl-testosterone 1a,17B-dimethy1-A -18-nor-androstad1en-3-one; 1a-methyl-17a-fin0ro-A androsten-B-one; and 1a-methyl-17 B- chlorofluoroacetoxy-Nandrosteu-H- one. methyl-testosterone methyl-17 ,S-methyl-M- -18-nor-androla-vinyl-testosteroudc lm-ethinyl-testosteroner la-propenyl-testosterone la-propinyl-testosterone l-methyl-A -androstadiena l7 8-0l-3-one.

Example VI A mixture of 500 mg. of 17a-iluoro-A -androsten-3- one, cc. of dioxane and 350 mg. of 2,3-dichlono-5,6- dicyano-lA-lbenzoquinone was refluxed for 10 hours. It was then cooled, the 2,3-dichloro-5,6-dicyano-1,4-benzohydroquinone formed during the reaction filtered off Example VII To a solution of 1 g. of 17ot-methyl-A -androstene- 3 8,17 ,8diol-17-acetate in cc. of anhydrous tetrahydrofuran, there was added 1.1 molar equivalents of 2- chloro-l,1,Z-trifluorotriethylamine and the reaction mixture was refluxed for 10 minutes and then evaporated to dryness under reduced pressure. The residue was puritied by chromatography on Florisil, thus producing the pure 3fi-fluoro-17u-methyl-A -androstem176-01 acetate.

By the same method A -and-rosten-3B-ol-17-one, 6- methyl-M-androsten-33-01-17=one and 17a-methyl-A -androstene-3B,llfl,l7fi-triol-ll, l7 dipropionate were converted respectively i-nto 3 8flnoro-A -androsten-17-one, 35 fluoro 6 methyl A androsten 3,6 o1 17 one and 3,8 fluoro 17a methyl A androstene 115,175- diol dipropionate.

Example VIII A solution of 2 g. of 3,B-fluorO-A androsten-3-one in 60 cc. of anhydrous benzene was added, under an atmosphere of nitrogen to a solution of potassium amyloxide previously prepared from 1.4 g. of potassium in cc. of amyl alcohol. A slow stream of purified acetylene was then introduced into the resulting solution for 40 hours and the solution was then poured into ice water and extracted with several portions of benzene. The combined extract was washed to neutral, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was chromatographed on 50 times its weight of washed alumina, and the solid fractions were recrystallized from acetonehexane, thus I yielding 3,8-fluoro-17a-ethinyl-A -androsten- 17,9-01.

To a solution of 500 mg. of the foregoing compound in 10 cc. of anhydrous benzene there were added 100 mg. of p-tol-uenesulfonic acid and 1.5 cc. of acetic anhydride and the mixture was allowed to stand \for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to efiect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from etherhexane produced the acetate of 3 8-fluoro-17a-ethinyl-A .a-ndrosten-l7fi-ol.

Example IX By following the method of Example I but using 2.2 molar equivalents of 2-ch1oro 1,1,2-trifluorot1iethylamine, A -androstene-3fi,17 6-diol was converted into fluoro17,8-met-hyl-A 18-nor-androstadiene, 35,17a-difluoro-A -androstene and 318-fluoro-17 3-ch1orofluoroacetoxy-A -androstene which were separated by chromatography on Florisil.

In a similar manner, starting from M-androstene- 3fi,l7;8-diol, there were produced 3,8-fiuoro-17B-methyl- 6 A -18-nor-androstadiene, 3p,17u-difluoro-A -androstene and 3B-fluoro-17B-chlorofluoroacetoxy-A -androstene.

I claim: 1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkinyl, and Z is selected from the group consisting of a double bond and a saturated linkage between C-1 and C-2.

2. l7a-fluoro-A -androsten-3-one.

3. 17a-iluoro-A -andr0stadien-3-one.

4. lot-methyl-l7a-fluoro-A -androsten-3 one.

5. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower :alkinyl, and Z is selected from the group consisting of a double bond and a saturated linkage between C-1 and C-2.

. 17,8-methyl-A d 8-nor-androstadien-3-one.

. l7 8-methyl-A -18-no-r-andnostatrien-3-one.

. 1,17fi-dimethyl-A -18 nor-androstatrien-3-one. 17a-fluoro-A -19-nor-androsten-3-one.

. 17,8-chl0rofluoroacetoxy A -19-nor androsten-S- 17B-methyl-A -18,19-bisnoraandrostadien-3-one.

35,17a-difluoro-A -androstene.

. 3;8-fluono-17p-chlorofluoroacetoxy-A -androstene. 3B-fluon0-17B-methyl-A -1S-nOr-androstadiene. 3p,17a-diflu0ro-A -androstene,

V ,2 2 7 7 7 v 7 8 20. 3fl-flu0ro-17 3-ch10rofiuoroacetoxy-A andmstene; OTHER REFERENCES 21. 3fl-fluo1 o-17 3-methy1-A -l8-nor-androstadiene. tx 1, 445 479 4 9 22. The acetate ofV3,8-flu0ro-l7a-ethinyl-A androsten iiiii gg za g gii i; and 95 (195 17 -01.

References Cited by the Examiner 6 5 (1963) v UNITED STATES PATENTS Westphall et a1.:,Be1'ichte 72, pp.11233-'42 (1939).

2,981,659 4/1961 Fonken et a1. 195-51 3,076,828 2/1963 Wettstein eta1. 260-397.45 LEWIS GoTrsPimary Examiner" 3,077,482 2/1963 Wettste-in et a1. 260397-.1 HENRY A.FRENCH," S i n X miner.

Mori-et a1: Chem. & Pharm; Bull; 11;! pagqs 684-85 

1. A COMPOUND OF THE FOLLOWING FORMULA: 